1-halomethyl-5alpha-androstanes and -delta1-androstenes and processes for their preparation



United States Patent This invention relates to novel steroids and totheir production.

More particularly, this invention is directed at 1halomethyI-Su-androstanes represented by the formula:

a s a U wherein R is an oxygen atom or the group 11 R 0 in which R ishydrogen, tetrahydropyranyl, or a hydrocarbon car-boxylic acyl group; Ris hydrogen, tetrahydropyranyl, or a hydrocarbon carboxylic acyl group;R is hydrogen, methyl, ethyl, or ethynyl; each of X and Y is chloro orfiuoro; and Z is a carbon-carbon single bond or a carbon-carbon doublebond. The Wavy line (5) embraces both the a and B configurations.

The hydrocarbon carboxylic acyl groups of the present invention willcontain less than 12 carbon atoms and may be of a straight, branched,cyclic or cyclic-aliphatic chain structure. These may be saturated,unsaturated or aromatic and optionally substituted by functional groupssuch as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxycontaining up to 12 carbon atoms, nitro, amino, halogeno, and the like.Typical esters thus include acetate, propionate, enanthate, benzoate,trimethyl-acetate, t-butylacetate, phonoxyacetate,cyclopentylpropionate, aminoacetate, fl-chloropropionate, adamantoate,and the like.

The compounds of this invention represented above are anabolic agentsand are accordingly useful in the treatment of debilatory conditionssuch as are encountered in old age, postoperative recuperation, and thelike. The l7m-ethynyl compounds, in addition, exhibit progestationalactivity and are thus useful in the control and regulation of fertility.

These compounds may be prepared according to the following reactionscheme:

3,371,087 Patented Feb. 27, 1968 O O J CH3 )OiCH: CHXY OXY I E in O (Iv)(III) O O 5 CH 0 R INWRZ OEXY CHXY E W l Z s O 5 (V Ir a wherein each ofR R R X, Y, and Z is as hereinbefore defined.

Referring to the above scheme, the starting steroid (I) is provided from5ot-androstan-17fi-ol-3-one upon conven: tional acylation of thel7-hydroxyl group with acetic anhydride in pyridine.

The u -unsaturation (II) is provided by brominating the saturatedstarting compound (I) followed by calcium carbonate treatment. The thusprepared A -ene is thereafter contacted with an alkali metal haloacetatenotably sodium trifluoroacetate, sodium trichloroacetate, or sodiumdichlorofiuoroacetate at a temperature above the decompositiontemperature of the salt employed, thus giving the 1,2-halomethylenederivative (III). This compound is then treated so as to effect openingof the fused cyclopropyl ring such as with zinc dust in acetic acid orother suitable reagents including zinc amalgams, for eX- ample,zinc-copper metal couple, in a variety of solvents such as the lowercarboxylic acids, organic alcohols, ethers, and hydrocarbons.

After the ring opening has been ellected, the thus prepared l-halomethylderivatives (IV) may be treated with bromine and calcium carbonate asdescribed above to reintroduce the N-unsaturation (V). Either thesaturated derivatives (IV) or the A -enes (V) are then elaborated at the0-17 position as follows.

If desired, the 17,8-acetoxy group can be removed upon base treatmentthus aiiording the l7p-hydroxy compound.

3 This 17,6-hydroxyl may be etherified with dihydropyran in the presenceof acid catalyst to yield the 17fi-tetrahY- dropyranyloxy ether.Alternatively, the secondary 17/3- hydroxyl can be esterified with anacylating agent such as adamantoyl chloride or acetic anhydride inpyridine.

In lieu of the above procedures, the 17,8-hydroxyl, provided upon basehydrolysis of the 17-acetate, may be oxidized such as with chromic acidto the l7-keto derivative. This 17-keto compound may then be treatedwith methylor ethylmagnesium bromide or methylor ethyllithium to givethe l7a-methyland l70c-Cthyl-l7B-OlS. The l7a-ethynyl-l7fi-ol steroid isprovided upon treatment of the l7-keto compound with acetylene in thepresence of potassium in organic solution. The 17a-ethyl group mayalternately be provided upon controlled hydrogenation of the l7a-ethynyl group, provided as above.

The tertiary l7i3-hydroxyl may be etherified as above or esterified withacylating agent in the presence of acid catalyst such as aceticanhydride in acetic acid, p-toluenesulfonic acid, and the like.

Before such elaboration of the Cl7 keto takes place, the 3-keto group ispreferably protected such as by forming the corresponding 3-ketal bytreatment with ethylene glycol in benzene in the presence ofptoluenesulfonic acid. This protecting group at C-3 is finally removedin the usual manner such as by acidic treatment to afford thecorresponding S-keto compound fully substituted at -17 (V1) as outlinedabove.

The restored 3-keto group may be reduced such as with sodium borohydridein methanol or lithium aluminum hydride in tetrahydrofuran to give the3fi-hydroxy steroid. This secondary hydroxyl may be esterified asdescribed above to afford the 3,8-ester or it may be etherified withdihydropyran in the presence of any stable sulfonyl chloride, preferablyp-toluene-sulfonyl chloride, benzenesulfonyl chloride, methanesulfonylchloride, and the like to give the 3,8-tetrahydropyranyloxy ether. Thusprovided are the products of this invention represented by Formula VII.

The following examples serve to illustrate the invention more fully butare not intended as limitations upon the scope hereof except insofar asindicated in the appended claims.

Example 1 A mixture of 1 g. of 5a-androstan-17B-ol-3-one, 4 ml. ofpyridine, and 2 ml. of acetic anhydride is allowed to stand at roomtemperature for hours. The mixture is then poured into ice Water and thesolid which forms is collected by filtration, washed with water anddried to yield 17p acetoxy 50: androstan-3-one which may be furtherpurified through recrystallization from acetone: hexane.

To a stirred solution of 1 g. of l7B-acetoxy-5a-androstan-3-one and 6.6g. of p-toluenesulfonic acid in 330 ml. of glacial acetic acid is added,over a 10-minute period, a solution of 1.1 molar equivalent of bromineand 2.45 g. of sodium acetate in 110 ml. of glacial acetic acid. Afterstirring for an additional 10-minute period, a solution of 75 g. ofsodium acetate in 150 ml. of glacial acetic acid is added and stirringis then continued at 20 C. for 5 minutes. The reaction mixture is nextpoured into 1 liter of ice Water and the solid which forms is collectedand dissolved in methylene chloride. This solution is washed with water,dilute sodium bicarbonate solution and water, dried and evaporated todryness. The residue is dissolved in 60 ml. of dimethylformamide andadded to a well stirred suspension of 12.5 g. of calcium carbonate in440 ml. of dimethylacetamide, heated at reflux. Refiuxing is continuedfor 45 minutes and the mixture is then filtered and concentrated toabout 60 ml. under reduced pressure. After the addition of 5 ml. ofhexane, the mixture is filtered and the filtrate is evaporated todryness. This residue is chromatographed on acid washed alumina with 3:1benzenezchloroform to yield l7fi-acetoxy-5u-androstl-en-3-one which maybe recrystallized from cyclohexane: ethyl acetate.

To a stirred and refluxing solution of l g. of 175-acet0xy-5a-androst-l-en-3-one in 8 ml. of dimethyl diethyleneglycolether is added in a dropwise fashion over a two-hour period, a solutionof 30 equivalents of sodium chlorodifluoroacetate in 30 ml. of dimethyldiethyleneglycol ether. At the end of the reaction period, which may befollowed by the UV. spectra, the mixture is filtered and evaporated invacuo to dryness. The residue is added to 10% methanolic potassiumhydroxide and this mixture is heated briefly at reflux and poured intoice Water. The solid which forms is collected, washed with water, driedand chromatographed on alumina, eluting with methylene chloride, toyield la,2a-difiuorornethylene-l7fiacetoxy-5a-androstan-3-one togetherwith the corresponding lp,2,8 difiuoromethylene derivative which may bereadily separated by chromatography.

The use of sodium trichloroacetate and sodium dichlorofiuoroacetate forsodium trifluoroacetate in the above procedure respectively provides thecorresponding 1,2 dichloromethylene and 1,2 chlorofluoromethylenederivatives.

A stirred solution of 16 g. of la,2a-difiuoromethylene-17B-acetoxy-5ix-androstan-3-one in 5 ml. of acetic acid is heated atreflux for 1 hour with several portions of zinc dust. The mixture isthen stirred at room temperature for 1 hour, filtered, the residue beingwashed with acetic acid, and diluted with 10 ml. of water. This mixtureis extracted with methylene chloride and the methylene chloride extractsare in turn washed with water, 2 N sodium bicarbonate solution, andWater. After drying this organic solution with magnesium sulfate, it isevaporated to dryness and chromatographed on alumina with hexane:methylene chloride followed by methylene chloriderethyl acetate to yieldla-dilluoromethyl-l-acetoxy-5a-androstan-3-one.

Treatment of the la-dihalomethyl steroid above with bromine and calciumcarbonate by the procedures given in paragraph two of this exampleaffords the correspondingl-dihalomethyl-l7fi-acetoxy-5a-androst-l-en-3-one.

Example 2 A solution of l g. of 1a-difiuoromethylNit-acetoxy-5ot-androstan-3-one in 50 ml. of methanol is heated at reflux for 3hours with a solution of potassium hydroxide in 1 ml. of Water. Thereaction mixture is then poured into ice water and the solid which formscollected by filtration, washed with Water to neutrality and dried toyield la-difiuOromethyI-Se-androstan-17,8-01-3-0ne which isrecrystallized from methylene chloridezether.

Two milliliters of dihydropyran are added to a solution of 1 g. of1a-difiuorOmethyI-Sa-androstan-17B-ol-3- one in 15 ml. of benzene. About1 ml. is removed by distillation to remove moisture and 0.4 g. ofp-toluenesulfonic acid is added to the cooled solution. This mixture isallowed to stand at room temperature for 4 days, and is then washed withaqueous sodium carbonate solution and water, dried and evaporated. Theresidue is chromatographed on neutral alumina, eluting with hexane, toyield 1a-difluoromethyl-17fl-tetrahydropyranyloxy 5a androstan 3 onewhich is recrystallized from pentane.

A mixture of 2 g. of 1a-difluoromethyl-Sa-androstan- -ol-3-one in 8 ml.of pyridine and 4 ml. of adamantoyl chloride is heated at steam bathtemperatures for one hour. The mixture is then poured into ice water andthe solid which forms is collected by filtration, washed with Water anddried to yield la-difluoromethyl-l7fi-adamantoyloxy 5a androstan 3 onewhich is further purified through recrystallization from methylenechloridezhexane.

Similarly, l-dihalomethyl-l7fi-acetoxy-5ot-androst-l-en- 3-0ne ishydrolyzed by the procedure given above to yieldl-dihalomethyl-u-androst-1-en-17B-ol-3-one. This compound is thentreated with dihydropyran as outlined above to yieldl-difiuoromethyl-l7fl-tetrahydropyranyloxy-5a-androst-l-en-3-one andwith adamantoyl chloride, similarly outlined .above to givel-difiuoromethyl-UB- adamantoyloxy-5ot-androst-1-en-3-one. In a similarmannor the corresponding 17/3-ethers and -esters of the otherltt-dihalornethyl steroids mentioned above are prepared. Otherl7fl-esters are prepared in accordance with the esterification proceduregiven above upon substitution of alternate acylating agents.

Example 3 A mixture of 1 g. ofla-difiuoromethyl-5a-androstanl7fi-ol-3-one, '25 ml. of dry benzene, 5ml. of ethylene glycol and 50 mg. of p-toluenesulfonic acid monohydrateis refluxed for 16 hours using a water separator. The reaction mixtureis then washed with aqueous sodium bicarbonate solution and Water, driedand evaporated .to dryness to yield1u-difiuoromethyl-3,3-ethylenedioxy-5aandrostan-l7fi-ol which isrecrystallized from acetone: hexane.

To a stirred solution of 1 g. of 1a-difluoromethyl-3,3-ethylenedioxy-Sa-androstan-17,8-01 in ml. of acetone, cooled to 0 C., isadded under nitrogen a solution of 8 N chromic acid (prepared by mixing26 g. of chromium trioxide with 23 ml. of concentrated sulfuric acid anddiluting with water to 100 ml.) until the color of the reagent persistsin the mixture, The mixture is then stirred for 5 minutes at 0-5 C. anddiluted with water. The solid which forms is collected by filtration,washed with water and dried under vacuum to yield lot-difluoromethyl-3,3-ethylenedi0xy-5a-androstan l7 one which may be further purified byrecrystallization from acetonez'hexane.

A solution of 5 g. of1a-difluoromethyl-3,3-ethylenedioxy-5a-androstan-17-one in 250 ml. ofthiophene-free benzene is treated with 27.5 ml. of 4 N methylmagnesiumbromide in anhydrous ether. The mixture is heated at reflux underanhydrous conditions for 3 hours, cooled, and cautiously treated withexcess aqueous ammonium chloride solution. This mixture is thenextracted with ethyl acetate and these extracts are in turn washed withwater, dried over sodium sulfate and evaporated to dryness to yield 1adifiuoromethyl 3,3 ethylenedioxy-Uamethyl-5a-androstan-17,8-01 which isrecrystallized from methylene chloride:hexane.

A mixture of 0.5 g. of1a-difiuorornethyl-3,3-ethylenedioxy-l7a-methyl-5a-androstan-l"/fi-ol in30 ml. of acetone and 50 mg. of p-toluenesulfonic acid is allowed tostand to room temperature for hours. It is then poured into ice waterand extracted with ethyl acetate. These extracts are washed with waterto neutrality, dried over sodium sulfate and evaporated to dryness. Theresidue is triturated with ether to yieldlot-difluoromethyl-lhmethyl-5a-androstan-17fl-ol-3-one which isrecrystallized from acetone:hexane.

Example 4 To a stirred solution of 2 g. of 1a-difluoromethyl-3,3-ethylenedioxy-5a-androstan-17-one in 250 ml. of absolute ether is addedin a dropwise fashion and under nitrogen, an ethereal solution of 10molar equivalents of ethyl lithium. The mixture is then stirred for 48hours at room temperature, poured into water, acidified withhydrochloric acid and stirred vigorously for 1 hour. The ethereal phaseis separated, washed with water to neutrality, dried over sodium sulfateand evaporated to dryness to yield1a-difiuoromethyl-3,3-ethylenedioxy-17otethyl 5o: androstan 17,8 01which is further purified through recrystallization from acetonezhexane.

Acid hydrolysis via the procedure given in the last paragraph of Example3 affords 1a-difiuoromethyl-Hot-ethyl- Sa-andrOstan-l7[3-ol-3-one.

6 Example 5 A solution of 1 g. of1a-difiuoromethyl-3,3-ethylene'dioxy-5a-androstan-17-one in 30 ml. ofanhydrous benzene is added under nitrogen to a solution of 1.4 g. ofpotassium in 30 ml. or" t-amyl alcohol. A slow current of purifiedacetylene is then passed through the solution for 40 hours. The mixtureis diluted with water and extracted with benzene. These extracts arewashed with water to neutrality, dried over sodium sulfate andevaporated. Chromatography of the residue on alkaline alumina with 2:3hexanezbenzene yields1a-difiuoromethyl-3,3-ethylenedioxy-l7a-ethynyl-5a-androstan-17,8-01which is recrystallized from acetonezhexane.

Acid hydrolysis as above in Example 3 (last paragraph) thereafter yieldslot-difluoromethyl-l7u-ethynyl- 5a-androstan-l76-ol-3-one.

Similarly, when 1-difiuoromethyl-5a-androst-1-en-17B- ol-3-one is usedas the starting steroid in Examples 3, 4, and 5, the respective productsobtained by each procedure after acid hydrolysis thereof arel-difiuoromethyl-l7a-methyl-5-a-androst-l-en-175-ol-3- one,

1-difluoromethyl-17a-ethyl-5a-androst-1-en-17/3-ol-3- one, and

l-difluoromethyl-17a-ethynyl-5a-androst-l-en-17,8-01-3- one.

In like manner, the other lot-dihalomethyl steroids of this inventionare converted to the corresponding l7a-substituted-l7/3-ols.

Example 6 A mixture of l g. of1a-difluoromethyl-l7ot-ethynyl-5uandrostan-l7fi-ol-3-oue, 1 g. ofp-toluenesulfonic acid monohydrate, 50 m1. of acetic acid and 25 ml. ofacetic anhydride is allowed to stand at room temperature for 24 hours,and then poured into water and stirred. This mixture is then extractedwith methylene chloride and these extracts are dried and evaporated toyield lot-difluoromethyl 17cc ethynyl 17B acetoxy-5ot-androstan- 3-onewhich is recrystallized from acetonezether.

By substituting propionic anhydride for acetic anhydride, thecorresponding 17/3-propionoxy steroid is obtained.

Among other steroids similarly prepared in accordance with the aboveprocedure utilizing the requisite starting 17,8-ols arel-difluoromethyl-l7a-ethynyl-l75-acetoxy-5aandrost l-en-3-one,lot-difluoromethyl-l7a-methyl-17fiacetoxy 5u-androstan-3-one,l-diiluoromethyl-17a-methyl 17fl-acetoxy-5u-an-drost-1-en-3*one,lot-difluoromethyl- 17cc ethyl 17fi-acetoxy-5u-androstan-3-one, and1-difluoromethyl 17a ethyl-17B-acetoxy5 z*androst-l-en-3- one as well asthe l7a-substituted-17f3-acetates of the other lot-dihalomethyl steroidshereof.

The above mentioned 17a-substituted-l7fl-ols may also be treated withdihydropyran following the procedure of the second paragraph of Example2 to thus yield the cor responding 17fi-tetrahydropyranyl ethersthereof. Thus, for example,lot-difiuoromethybl7a-ethynyl-17p-tetrahydropyranyloxy-5ot-androstan-3-one,l-difluoromethyl-Uw ethynyl 17p tetrahydropyranyloxy 5a androst 1- en 3one, and la difluoromethyl 17w ethyl 17/3tetrahydropyranyloxy-5a-androstan-3-one are prepared as well as theethers of the other above named l7a-SLlbstituted-17p-o1 steroids.

Example 7 A solution of 1 g. of sodium borohy-dride in 3 ml. of Water isadded to an ice-cooled solution of l g. of 10!. difluoromethylHot-ethynyl-l7p-tetrahydropyranyloxy-5a-androstan-3 one in ml. ofmethanol and the mixture then allowed to stand for 16 hours at roomtemperature. The excess reagent is decomposed by addition of acetic acidand the solution is then concentrated to small volume in vacuo anddiluted with water. The product is extracted with ethyl acetate andthese extracts are washed with Water, dried and evaporated to yield1u-difiuoromethyl 17a ethynyl17fi-tetrahydropyranyloxya-androstan-3fi-ol which may be furtherpurified by recrystallization from acetonezhexane.

The thus reduced steroid is esterified by the procedure of Example 2,paragraph 3 to yield 1a-difluoromethyl-3fiadamantoyloxy 17a ethynylUri-tetrahydropyranyloxy-5u-androstane.

The 3B-acetoxy may be provided therein by allowing a mixture of 1 g. ofla-difiuoromethyl-17ot-ethynyl-17fltetrahydropyranyloxy-Sa-androstan-3fi-ol,4 ml. of pyridine, and 2 ml. of acetic anhydride to stand at roomtemperature for hours. The mixture is then poured into ice water and thesolid which forms is collected by filtration, washed with water anddried to yield lot-difiUOl'O- methyl 3/3acetoxy-17ot-ethynyl-Uri-tetrahydropyranyloxy-fia-androstane which maybe further purified through recrystallization from acetonezhexane.

The 3(i-tetrahydropyranyloxy group may be provided by the followingprocedure:

Two milliliters of dihydropyran are added to a solution of 1 g. of1a-ditluoromethyl-l7a-ethynyl-17B-tetrahydropyranyloxy-5a-androstan-3/3-olin 15 ml. of benzene. About 1 ml. is removed by distillation to removemoisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooledsolution. This mixture is allowed to stand at room temperature for fourdays, and is then washed with aqueous sodium carbonate solution andwater, dried and evaporated. The residue is chromatographed on neutralalumina, eluting with hexane, to yield lot-difluoromethyl- 3,8,175bis(tetrahydropyranyloxy) 17a ethynyl-Saandrostane which isrecrystallized from pentane.

Thus also prepared via the above procedure is lot-difiuorornethyl 3/3tetrahydropyranyloxy Hot-ethynyl- 17,8-acetoxy-5ot-androstane from thecorresponding reduced steroid.

The above bisether may also be prepared upon similar treatment with twoequivalents of dihydropyran from 1adifluoromethyl 17oz ethynyl5ot-androstane-3 3,17fldiol which is obtained from the corresponding3-keto compound upon reduction following the procedure of the firstparagraph hereof. Thus also prepared is l-difiuoromethyl 35,173tetrahydropyranyloxy 17CL'ITlthy1-5OL- androst-l-ene.

Similarly, by following the procedures outlined in this example upon theother steroids of this invention, the corresponding 3-substitutedderivatives are prepared. Thus, by way of illustration,1-difiuoromethyl-3B,17B- diacetoxy-17a-ethyl-5ot-androst-l-ene isprepared from 1 difluoromethyl 17cc ethyl 176 acetoxy5aandrost-l-en-B-one hereby.

Examples 2 through 7 have been illustrated utilizing steroids containingthe lot-dihalomethyl group. These procedures may be practiced upon thecorresponding 15- dihalomethyl steroids with similar results.

What is claimed is: 1. Steroids of the formula 1 tm CHXY Z Z H R o inwhich R is hydrogen, tetrahydrpyranyl, or a hydrocarbon carboxylic acylgroup; R is hydrogen, tetrahydropyranyl, or a hydrocarbon carboxylicacyl group; R is hydrogen, methyl, ethyl, or ethynyl; each of X and Y ischloro or fluoro; and Z is a carbon-carbon single bond or acarbon-carbon double bond.

2. Steroids of claim 1 wherein each of X and Y is fluoro.

3. Steroids of claim 2 wherein Z is a carbon-carbon single bond.

4. A steroid of claim 3 wherein R is an oxygen atom, R is acetyl, and Ris ethynyl.

'5. A steroid of claim 3 wherein R is an oxygen atom, R istetrahydropyranyl, and R is ethyl.

6. A steroid of claim 3 wherein R is the group H THO-5 in which R istetrahydropyranyl, R is acetyl, and R is ethynyl.

7. Steroids of claim 2 wherein Z is a carbon-carbon double bond.

8. A steroid of claim 7 wherein R is the group R 0 in which R istetrahydropyranyl, R is tetrahydropyranyl, and R is methyl.

9. A steroid of claim 7 wherein R is the group IMO- in which R isacetyl, R is acetyl, and R is ethyl.

10. A steroid of claim 7 wherein R is an oxygen atom, R is hydrogen, andR is methyl.

References Cited UNITED STATES PATENTS 3,228,837 1/1966 Kaspar et al.167--74 LEWIS GOTTS, Primary Examiner.

T. M. MESHBESHER, Assistant Examiner.

1. STEROIDS OF THE FORMULA